Neuronal death, which follows ischemic injury or is triggered by excitotoxins, can occur by both apoptosis and necrosis. Caspases, which are not directly required for necrotic cell death, are central mediators of the apoptotic program. Here we demonstrate that caspases cleave and inactivate the plasma membrane Ca 2+ pump (PMCA) in neurons and non-neuronal cells undergoing apoptosis. PMCA cleavage impairs intracellular Ca 2+ handling, which results in Ca 2+ overload. Expression of non-cleavable PMCA mutants prevents the disturbance in Ca 2+ handling, slows down the kinetics of apoptosis, and markedly delays secondary cell lysis (necrosis). These findings suggest that caspase-mediated cleavage and inactivation of PMCAs can lead to necrosis, an event that is reduced by caspase inhibitors in brain ischemia.

BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). We report one-and two-year longitudinal data to delineate potential outcomes for clinical trials. MethodsWe enrolled genetically confirmed FRDA patients from eleven European study sites. Patients were seen on an annual basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF) and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analyzed with linear mixed effect models. This study is registered with ClinicalTrials.gov, number NCT02069509. Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0·09 [0·02] per additional 100 repeats). Annual worsening for INAS was 0·10 (0·03), for SCAFI -0·04 (0·01), for ADL 0·93 (0·06) and for EQ-5D-3L -0·02 (0·004). PVF performance improved by 0·99 [0·14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.

BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). Based on our 1 year and 2 year data we aimed to delineate potential outcomes for clinical trials. MethodsWe enrolled patients with genetically confirmed FRDA from 11 European study sites. Patients were seen on an yearly basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analysed with linear mixed effect models.This study is registered with ClinicalTrials.gov, number NCT02069509. Findings 605 FRDA patients were enrolled between 15-Sep-2010 and 21-Nov-2013. 546 patients (90%) contributed data with at least one follow-up visit. Annual progression rate for SARA was 0•77 points (SE 0•06) in the overall cohort. Deterioration in SARA was associated with a lower age of onset (by -0•02 [0•01] points per year) and a lower SARA baseline score (-0•07 [0•01] per baseline-point). Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0•09 [0•02] per additional 100 repeats).Annual worsening for INAS was 0•10 (0•03), for SCAFI -0•04 (0•01), for ADL 0•93 (0•06) and for EQ-5D-3L -0•02 (0•004). PVF performance improved by 0•99 [0•14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.